ALPRAZOLAM COMBIX 0.25 mg TABLETS

2. What you need to know before taking Alprazolam Combix

Do not take Alprazolam Combix

• if you are allergic to alprazolam, benzodiazepines, or any of the other components of this medicine (listed in section 6)
• if you have breathing difficulties related or not to sleep (sleep apnea)
• if you have a disease called myasthenia gravis, characterized by muscle weakness
• if you have severe liver disorders.

Warnings and precautions

Consult your doctor or pharmacist before starting to take Alprazolam Combix

• If you have any lung, kidney, or liver problems.
• If you have felt or feel so depressed that you have had thoughts or ideas of suicide.
• After continuous use of alprazolam, some loss of efficacy (tolerance) may be detected.
• There is a risk of developing addiction/dependence when using alprazolam.
• If during treatment you notice symptoms of mania (state of overexcitement, feeling of euphoria, or hyperirritability) or hypomania (state of excitement and excessive activity).
• Treatment with benzodiazepines, including alprazolam, may cause dependence, mainly after uninterrupted use of the medicine for a long time.

To minimize the risk of dependence, the following precautions should be taken into account:

• The use of benzodiazepines will only be done under medical prescription (never because they have worked for other patients) and will never be recommended to other people.
• Do not increase the prescribed doses in any way, nor prolong treatment for longer than recommended.
• Consult your doctor regularly so that they can decide if you should continue treatment.
• Do not combine several benzodiazepines, regardless of their indication.
• When stopping treatment with alprazolam, symptoms similar to those that led you to start treatment with alprazolam (rebound effect) may appear. To avoid this, it is recommended not to interrupt treatment abruptly, but to gradually reduce the dose, according to the doctor's instructions (see section "If you stop taking Alprazolam Combix").
• The use of alprazolam together with opioid medications can cause deep sedation, respiratory depression, coma, and death.
• Benzodiazepines can cause memory loss and reactions such as:

restlessness, agitation, irritability, aggression, delirium, fits of rage, nightmares, hallucinations, psychosis, inappropriate behavior, and other adverse effects on behavior. If this happens, you should stop treatment and consult your doctor.

• It is very important that you inform your doctor if you have a history of drug and alcohol use.

Other medicines and Alprazolam Combix

Tell your doctor or pharmacist if you are taking, have recently taken, or may need to take any other medicine.

Alprazolam may interact with other medicines. Inform your doctor or pharmacist if you are taking any of the following medicines:

• Central nervous system depressants, as they may enhance the sedative effect of alprazolam:

• Major tranquilizers (antipsychotics).
• Sleep inducers (hypnotics).
• Medicines used to treat depression.
• Medicines for the treatment of epilepsy (antiepileptics).
• Narcotic analgesics and opioids (morphine derivatives), as they may increase the feeling of euphoria, which can lead to increased psychological dependence.
• Medicines used for the treatment of anxiety (anxiolytics/sedatives).
• Anesthetics.
• Sedating antihistamines (medicines for treating allergies).
• The concomitant use of alprazolam and opioids (potent analgesics, medications for substitution therapy (treatment of opioid addiction), and some cough medications) increases the risk of somnolence, difficulty breathing (respiratory depression), coma, and can be potentially fatal. Due to this, concomitant use should only be considered when other treatment options are not possible.

However, if your doctor prescribes alprazolam together with opioids, the dose and duration of concomitant treatment should be limited by your doctor.

• Tell your doctor about all opioid medications you are taking and closely follow your doctor's recommended dose. It may be helpful to inform friends or family members so that

they are aware of the signs and symptoms indicated above. Contact your doctor if you experience any of these symptoms.

• There are groups of medicines that, due to their action in the body (cytochrome P450 inhibitors), may interact with alprazolam and, in some cases, increase its activity. Some of the medicines that may interact with alprazolam are:

• Medicines used to treat fungal infections, such as ketoconazole, itraconazole, posaconazole, or voriconazole. It is not recommended to take them at the same time as alprazolam.
• The following antidepressants: nefazodone, fluvoxamine, and fluoxetine.
• Gastric protectors, such as cimetidine.
• Dextropropoxyphene (narcotic analgesic).
• Oral contraceptives.
• Diltiazem (antihypertensive).
• Macrolide antibiotics, such as erythromycin, troleandomycin, clarithromycin, and telithromycin.
• Medicines used to treat AIDS, such as ritonavir, etc.
• Digoxin (medicine used to suppress or prevent heart rhythm disorders).

Taking Alprazolam Combix with food, drinks, and alcohol

During treatment, avoid alcoholic beverages. The effect of alcohol can enhance sedation, which can affect your alertness (see section "Driving and using machines").

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Alprazolam is not recommended during pregnancy or breastfeeding, unless, in the doctor's opinion, the benefit outweighs the risk to the child.

If alprazolam is administered during late pregnancy or during childbirth, effects on the newborn, such as decreased body temperature (hypothermia), decreased muscle tone (hypotonia), and moderate respiratory depression, may occur.

Children born to mothers who take benzodiazepines chronically during the last period of pregnancy may develop physical dependence, which can trigger a withdrawal syndrome in the postnatal period.

Use in children and adolescents (under 18 years)

Alprazolam is not recommended for children and adolescents under 18 years. Benzodiazepines should not be administered to children unless strictly necessary and prescribed by a doctor. The efficacy and safety of alprazolam in children under 18 years have not been established.

Use in elderly patients (over 65 years)

Alprazolam may affect this group of patients more than younger patients. If you belong to this group, your doctor may reduce the dose and check your response to treatment. Please follow their instructions carefully (see the section "How to take Alprazolam Combix").

Benzodiazepines and related products should be used with caution in elderly patients due to the risk of sedation and/or musculoskeletal weakness, which can cause falls, often with serious consequences in this population.

Special patient groups

If your liver or kidneys do not function properly, consult your doctor, who may advise you to use a lower dose of alprazolam.

If you have respiratory disorders, inform your doctor.

Driving and using machines

Alprazolam may alter your ability to drive or operate machinery, as it can cause drowsiness, decrease your attention, or decrease your reaction capacity. The appearance of these effects is more likely at the start of treatment or when the dose is increased. Do not drive or use machines if you experience any of these effects.

These effects can be enhanced if you consume alcohol at the same time.

Alprazolam Combix contains lactose monohydrate and sodium benzoate (E-211)

If your doctor has told you that you have an intolerance to certain sugars, consult them before taking this medicine.

This medicine contains 0.15 mg of sodium benzoate (E-211) per tablet.

If you need additional information on this point, consult your doctor or pharmacist.

3. How to take Alprazolam Combix

Follow your doctor's instructions for taking this medicine exactly. If in doubt, consult your doctor or pharmacist again.

Dosage:

The tablet or part of it should be swallowed without chewing, with a little liquid. Your doctor will prescribe the most suitable presentation of alprazolam, according to the dose you need.

The recommended dose is:

• For the treatment of anxiety states and anxiety associated with symptoms of depression:
• The initial dose is 0.25 mg to 0.5 mg of alprazolam, three times a day.
• The usual dose ranges from 0.5 mg to a maximum of 4 mg per day, divided into 3 or 4 doses.

• For the treatment of anxiety disorders:
• A initial dose of 0.5 mg to 1 mg of alprazolam at bedtime is recommended.
• Subsequently, your doctor will adjust the dose based on your response to treatment. Dose adjustments should be made in increments not exceeding 1 mg every 3 or 4 days. Additional doses may be added until the dosing regimen of 3 or 4 times a day is reached.

In elderly patients, with chronic respiratory insufficiency, liver or kidney impairment, the recommended initial dose is 0.25 mg of alprazolam, 2 or 3 times a day, with the total daily dose of alprazolam being 0.5 mg to 0.75 mg in divided doses, which may be gradually increased if necessary and well tolerated.

Each individual dose should not exceed the indicated limits, and the total daily dose should not either, unless your doctor explicitly indicates otherwise.

Duration and discontinuation of treatment:

The duration of treatment should be as short as possible (not exceeding 12 weeks, including the withdrawal period). If your doctor considers it necessary to prolong treatment, they will do so for limited periods and will closely monitor your situation.

Never stop treatment abruptly. Your doctor will indicate the duration of treatment based on the evolution of your disease and will explain how to gradually reduce the dose until the end of treatment.

If you think the effect of alprazolam is too strong or too weak, tell your doctor or pharmacist.

If you take more Alprazolam Combix than you should

If you have taken more alprazolam than you should, consult your doctor or pharmacist immediately or go to the nearest hospital, taking this leaflet with you.

Overdose with benzodiazepines is usually manifested by different degrees of central nervous system depression, ranging from drowsiness to coma. Symptoms include drowsiness (drowsiness), speech disorders (dysarthria), coordination disorders, confusion, lethargy (state of deep and prolonged drowsiness), decreased muscle tone (hypotonia), decreased blood pressure, respiratory depression, rarely coma, and very rarely death. Serious sequelae are rare, unless alprazolam is taken with other medications or alcohol.

In case of overdose or accidental ingestion, consult the Toxicology Information Service, phone 91 562 04 20, indicating the medicine and the amount taken.

If you forget to take Alprazolam Combix

Do not take a double dose to make up for forgotten doses. If the forgotten dose is recent, take your dose immediately, and if not, wait for the next dose without taking a double dose to make up for it.

If you stop taking Alprazolam Combix

Treatment with alprazolam can produce dependence, so when stopping alprazolam abruptly, withdrawal symptoms may appear.

The withdrawal symptoms that may occur are: headache, muscle pain, anxiety, tension, restlessness, confusion, irritability, general feeling of discomfort (dysphoria), insomnia, intolerance to light, sounds, and physical contact, tingling and cramps in the limbs and abdomen, vomiting, sweating, tremors, depersonalization, hallucinations, and convulsions. If this happens, you should consult your doctor immediately.

If you have any other questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

The adverse effects that may appear during treatment with alprazolam occur predominantly at the beginning of treatment and generally disappear with continued administration or after a reduction in dose.

Very frequent adverse effects (may affect more than 1 in 10 people):

• Depression.
• Sedation, somnolence, coordination disorder (ataxia), memory alteration, difficulty articulating words (dysarthria), dizziness, headache.
• Constipation, dry mouth.
• Fatigue, irritability.

Frequent adverse effects (may affect up to 1 in 10 people):

• Feeling of confusion, disorientation, alteration of sexual desire (libido), anxiety, difficulty sleeping (insomnia), nervousness.
• Abnormal coordination, balance alteration, difficulty concentrating, excessive sleepiness (hypersomnia), state of deep and prolonged drowsiness (lethargy), tremor.
• Nausea, decreased appetite.
• Blurred vision.
• Dermatitis.
• Sexual dysfunction.
• Weight changes.

Uncommon adverse effects (may affect up to 1 in 100 people):

• Mental and behavioral disorders (mania), hallucinations, anger reactions, agitation, dependence.
• Memory loss (amnesia).
• Muscle weakness.
• Inability to retain urine in the bladder (urinary incontinence).
• Irregular menstruation.
• Withdrawal symptoms.

Frequency not known (cannot be estimated from available data):

• Increased prolactin levels in the blood (hormone responsible for stimulating and maintaining lactation after childbirth).
• Mental and behavioral disorders (hypomania), aggressiveness, hostility, abnormal thinking, psychomotor hyperactivity, drug abuse.
• Autonomic nervous system imbalance, involuntary muscle contractions (dystonia).
• Gastrointestinal disorder, hepatitis, liver function alteration, yellowing of the skin and whites of the eyes (jaundice).
• Peripheral edema.
• Angioedema (swelling under the skin surface).
• Photosensitivity (exaggerated response to light).
• Urinary retention in the bladder.
• Elevated intraocular pressure.

With the use of benzodiazepines, the following may appear:

• Somnolence, lack of reaction to emotional stimuli (emotional blunting), reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision. These phenomena occur predominantly at the beginning of treatment and generally disappear with continued administration. Gastrointestinal alterations, changes in sexual desire, or skin reactions may occasionally occur.
• A loss of memory (amnesia) may develop, which may be associated with inappropriate behavior.
• The use of benzodiazepines may unmask a pre-existing depression.
• When using benzodiazepines or similar compounds, reactions such as restlessness, agitation, irritability, aggressiveness, delirium, rage attacks, nightmares, hallucinations, psychosis, inappropriate behavior, and other behavioral alterations may appear. These reactions may be severe and occur more frequently in children and the elderly.
• Administration of the product (even at usual doses) may lead to the development of physical dependence. Discontinuation of treatment may lead to the development of withdrawal or rebound phenomena. Psychic dependence may occur. Cases of abuse have been reported.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Alprazolam Combix

Keep this medicine out of sight and reach of children.

This medicine does not require special storage conditions.

Do not use this medicine after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Medicines should not be thrown away through drains or into the trash. Deposit the packaging and medicines you no longer need at the SIGRE Point in the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This way, you will help protect the environment.

6. Package Contents and Additional Information

Composition of Alprazolam Combix 0.25 mg EFG Tablets

• The active ingredient is alprazolam, each tablet contains 0.25 mg.
• The other components are: lactose monohydrate, microcrystalline cellulose, pregelatinized corn starch, sodium docusate, sodium benzoate (E-211), anhydrous colloidal silica, magnesium stearate, and yellow colorant PB-22877 (composed of lactose monohydrate and quinoline yellow (E-104)).

Appearance of the Product and Package Contents

Alprazolam Combix 0.25 mg are uncoated yellow tablets, biconvex, round, and scored on one side.

The tablets are presented in PVC-Aluminum blisters in boxes of 30 tablets.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Combix Laboratories, S.L.U.

C/ Badajoz 2, Building 2

28223 Pozuelo de Alarcón (Madrid)

Spain

Manufacturer

Bluepharma - Indústria Farmacêutica, S.A.

• Martinho do Bispo

3045-016 Coimbra

Portugal

Date of the Last Revision of this Prospectus: February 2022

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/